Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non- canonical Wnt signaling pathways; still, no human variant in Wnt-pathway genes have been connected directly to ASD-relevant brain pathology. Recently, however, we discovered two families with ASD-specific mutations in PRICKLE2 (PK2). In vitro, recombinant mutant PK2s displayed a lowered affinity for PSD-95, another protein implicated in ASDs. Moreover, hippocampal neurons isolated from Prickle2-null (Pk2-/-) mice assumed an abnormal morphology and generated less spontaneous quantal synaptic activity; in complementation assays, these defects in hippocampal neurons were not rescued with the mutant forms of human PK2, suggesting these mutants lacked critical functions. Further behavioral studies in Pk2-/- mice showed their behavior mirrored ASD-like behaviors in humans. These studies provide new insight into the biological roles of PRICKLE2, its behavioral importance, and more firmly link Wnt-signaling abnormalities to ASDs. Our preliminary findings led us to the hypothesis that Wnt-modulating reagents represent an unexplored class of ASD treatments. Our long-term goals are to develop safer and more effective drug regimens for treating ASDs. The objective of this R21 application is to determine whether Wnt-modulating reagents alleviate the synaptic abnormalities observed in Pk2-/- neurons and the ASD-associated behaviors in Pk2-/- mice. The studies proposed here should both further our understanding of the biology of Wnt signaling and its connection to behavior, and lead to new therapeutic modalities. !